For many life-threatening diseases, organ transplantation is considered a standard treatment and, in many cases, the only alternative to certain death. The immune response to foreign cell surface antigens on the graft, encoded by the major histocompatibility complex (MHC) and present on all cells, generally precludes successful transplantation of tissues and organs unless the transplant tissues come from a compatible donor or the normal immune response is suppressed. The best compatibility and thus, long term rates of engraftment, are achieved using MHC identical sibling donors or MHC identical unrelated cadaver donors (Strom, 1989, supra; Strom, 1990, Clinical Aspects of Autoimmunity 4:8-19).
The host response to an organ allograft involves a complex series of cellular interactions among T and B lymphocytes as well as macrophages or dendritic cells that recognize and are activated by a foreign antigen (Strom, 1989, supra; Strom, 1990, Clinical Aspects of Autoimmunity 4:8-19). Co-stimulatory factors, primarily cytokines, and specific cell--cell interactions, provided by activated accessory cells such as macrophages or dendritic cells are essential for T cell proliferation. These macrophages and dendritic cells either directly adhere to T cells through specific adhesion proteins or secrete cytokines that stimulate T cells, such as IL-1 and IL-6 (Strom, 1989, In: Organ Transplantation: Current Clinical and Immunological Concepts: 4:8-19; Strom, 1990, Clinical Aspects of Autoimmunity 4:8-19).
IL-1 induces expression of the IL-6 gene in accessory cells. Accessory cell-derived co-stimulatory signals stimulate activation of interleukin-2 (IL-2) gene transcription and expression of high affinity IL-2 receptors in T cells (Pankewycz, et al., 1989 Transplantation 47:318; Cantrell, et al., Science 224:1312; Williams, et al., 1984 J. Immunol. 132:2330-2337). IL-2, a 15 kDa protein, is secreted by T lymphocytes upon antigen stimulation and is required for normal immune responsiveness. IL-2 stimulates lymphoid cells to proliferate and differentiate by binding to IL-2 specific cell surface receptors (IL-2R). IL-2 also initiates helper cell activation of cytotoxic T cells and stimulates secretion of .gamma.-interferon (.gamma.-IFN) which in turn activates cytodestructive properties of macrophages (Farrar, et al., 1981 J. Immunol. 126:1120-1125). Furthermore, .gamma.-IFN and IL-4 are also important activators of MHC class II expression in the transplanted organ, thereby further expanding the rejection cascade by actually making the grafted organ more immunogenic (Pober, et al., 1983, J. Exp. Med., 157:1339; Kelley, et al., 1984 J. Immunol., 132:240-245).
Similar mechanisms are involved in the development of autoimmune disease, such as type I diabetes. In humans and non-obese diabetic mice (NOD), insulin-dependent diabetes mellitus (IDDM) results from a spontaneous T-cell dependent autoimmune destruction of insulin-producing pancreatic .beta. cells that intensifies with age. The process is preceded by infiltration of the islets with mononuclear cells (insulitis), primarily composed of T lymphocytes (Bottazzo, G. F., et al., 1985, J. Engl. J. Med., 113:353; Miyazaki, A., et al., 1985, Clin. Exp. Immunol., 60:622). A delicate balance between autoaggressive T-cells and suppressor-type immune phenomena determine whether expression of autoimmunity is limited to insulitis or progresses to IDDM. In NOD mice, a model of human IDDM, therapeutic strategies that target T-cells have been successful in preventing IDDM (Makino, et al., 1980, Exp. Anim., 29:1). These include neonatal thymectomy, administration of cyclosporine A, and infusion of anti-pan T-cell, anti-CD4, or anti-CD25 (IL-2R) mAbs (Tarui, et al., 1986, Insulitis and Type I Diabetes. Lessons from the NOD Mouse. Academic Press, Tokyo, p. 143).
The aim of all rejection prevention and reversal strategies is to suppress the patient's immune reactivity to the graft, with a minimum of morbidity and mortality. Existing immunosuppressive therapies include administration of immunosuppressive compounds such as cyclosporine A, FK506 and rapamycin (First, 1992 Transplantation, 53:1-11). Because these agents inhibit proliferation of T cells generally, systemic treatment of patients leads to systemic immunosuppression which carries with it potential complications, including increase risk of infections and cancer (Wilkinson, et al., Transplant, 47:293-296; Penn, 1991 Transplant Proc., 23:1101; Beveridge, et al., 1984 Lancet, 1:788). In addition, these immunosuppressive agents cause considerable side effects, including nephrotoxicity, hepatotoxicity, hypertension, hirsutism, and neurotoxicity (Strom, 1989, supra; Strom, 1990, Clinical Aspects of Autoimmunity, 4:8-19; Tilney, et al., 1991 Ann Surg., 214:42-49; Myers, et al., 1984 N. Engl. J. Med., 311:699).
Administration of monoclonal antibodies against the T cell-specific antigen CD3 has been shown to block acute allograft rejection (Mackie, et al., 1990 Transplantation, 49:1150). Antibodies directed against the IL-2 receptor, T cell receptor, CD4, and certain cell adhesion molecules such as ICAM-1 have been used (Cosimi, et al., 1990 Surgery, 108:406; Cosimi, et al., 1990 J. Immunol., 144:4604; Strom et al., 1989 Kidney Int., 35:1026; Walz, 1990 Transplantation, 49:198-201). Anti-IL-2 receptor antibodies have been shown to bring about improved patient and graft survival (Soulillou, et al., 1990 N. Engl. J. Med., 322:1175).
Two novel cytokines, TGF-.beta. and IL-10, have recently been identified. These proteins have immunosuppressive activity, and apparently act via different mechanisms on the immune system (Moore, et al., 1990 Science, 248:1230-1234; Vieira, et al., 1991 Proc. Natl. Acad. Sci USA, 88:1172-1176; Barnard, et al., 1990 Biochim Biophys. Acta, 1032:79-87; Derynck, et al., 1985 Nature, 316:701-705).
TGF-.beta. exhibits potent immunosuppressive effects including inhibition of B and T cell activation and differentiation and deactivation of activated macrophages (Barnard, et al., 1990 Biochim Biophys. Acta, 1032:79-87; Roberts et al., 1990 Handbook of Experimental Pharmacology, 95:419-472). In particular, TGF-.beta. inhibits expression of immunoglobulin genes in B cells, decreases IL-2 induced T cell proliferation and differentiation of cytotoxic T cells, and inhibits MHC class II antigen expression on a number of cell types (Kehrl, et al., 1986 J. Exp. Med., 163:1037-1050; Ruegemer, et al., 1990 J. Immunol., 144:1767-1776; Cross, et al., 1990 J. Immunol., 144:432-439; Nelson, et al., 1991 J. Immunol., 146:1849-1857; Lee, et al., 1987 J. Exp. Med., 166:1290-1299; Wright, et al., 1986 Diabetes, 353:1174-1177). TGF-.beta. has been shown to inhibit pancreatic islet allograft rejection in mice, suggesting its potential use as an immunosuppressive agent. TGF-.beta. is produced by many different cell types, including macrophages, B and T cells, lung and mesenchymal cells, skin cells, platelets, and bone cells (Barnard, et al., 1990 Biochim Biophys. Acta, 1032:79-87; Roberts et al., 1990 Handbook of Experimental Pharmacology, 95:419-472). In addition, some cancer patients have been observed to show signs of immunosuppression due to secretion of TGF-.beta. by the cancer cells (Barnard, et al., 1990 Biochim Biophys. Acta, 1032:79-87; Roberts et al., 1990 Handbook of Experimental Pharmacology, 95:419-472; Siepl, et al., 1988 Eur. J. Immunol., 18:593-600).
IL-10 was first identified as a product of activated T.sub.H 2 T helper cells with the ability to inhibit macrophage-dependent cytokine synthesis in T.sub.H 1 T helper cells (Fiorentino, et al., 1989 J. Exp. Med., 170:2081). IL-10 appears to be expressed by several different hematopoietic cell types, including activated T.sub.H 2 cells, activated macrophages, mast cells, and B cells (Moore, et al., 1990 Science, 248:1230-1234; O'Barra, et al., 1990 Int. Immunol., 2:821; De Waal Malefyt, et al., 1991 J. Exp. Med., 174:1209-1220). IL-10 appears to inhibit the expression of a number of cytokines in macrophages, including interleukin-6 (IL-6), interleukin-1 (IL-1), interleukin-8 (IL-8), tumor necrosis factor-.alpha. (TNF-.alpha.), granulocyte/macrophage colony stimulatory factor (GM-CSF) and granulocyte colony stimulatory factor (G-CSF). IL-10 diminishes the antigen-presenting capacity of macrophages via downregulation of MHC class II gene expression on macrophages, and induces expression of MHC class II genes, but not class I genes in unstimulated splenic B cells (Go, et al., 1990 J. Exp. Med., 172:1625-1631; De Waal Malefyt, et al., 1991 J. Exp. Med., 174:915-924).